The degree of control that an organism can exercise over a stressor is arguably the most important modulator of the behavioral and physiological consequences of the stressor. Exposure to an uncontrollable stressor (IS, inescapable shock) in a rat results in a constellation of behavioral, neural, and immunological changes that do not occur if the stressor is controllable (ES, escapable shock). These effects have been termed "learned helplessness" or "behavioral depression" and mirror a number of important features of posttraumatic stress disorder and depression. The behavioral effect following IS central to this proposal is potentiated drug reward. In prior studies one of the other effects of uncontrollable stress, poor escape learning, was shown to be blunted if the organism experienced ES before IS. In a sense, the prior ES "immunized" the organism from the effects normally engendered by a subsequent experience with IS. Recently, the medial prefrontal cortex (mPFC) has been argued to be the structure that "detects" the controllability of a stressor. This structure can differentially modulate stress as well as reward circuits in the brain and can be regarded as a critical region modulating whether learned helplessness behaviors will be observed. The objective of this proposal is to characterize the changes that occur in the mPFC during ES that immunizes a rat from the potentiated drug reward normally observed following IS. These resilience effects will be studied by determining (a) if mPFC activation state during prior ES will modulate the ability of ES to block IS-potentiated morphine conditioned place preference (CPP) (b) the modulation of morphine's neurochemical effects when ES precedes IS (c) the generality and duration of prior experience with ES on reward-related paradigms. Neurochemical and behavioral changes after drug administration will be assayed by in vivo microdialysis, CPP, and psychomotor activation. The results from these experiments will help evaluate the hypothesis that activation of the mPFC during a stressor is necessary and sufficient to block potentiated drug reward, despite the controllability of the stressor. Relevance: Uncontrollable stressors such as rape, terrorist attacks, Hurricane Katrina, and automobile accidents are traumatic events that can lead to drug addiction/relapse as well as psychiatric conditions that are comorbid with drug addiction. However, not all people who experience such distressing life events develop drug addictions or mental illnesses; this difference in reactions to such events has led to the study of resiliency. A study that examines how an organism becomes resilient to drug addiction/relapse after an uncontrollable stressor could contribute to an advance in therapies that will promote resilience after a traumatic life event. [unreadable] [unreadable] [unreadable]